WO2010065803 Substituted piperidine spiro pyrrolidinone and piperidinones used as H3 modulators

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Biological target:

Histamine H3 receptor: H3

Activity:

Modulator

Steps Conditions Reactions
a p-toluene-sulfonyl chloride, DMAP, CH2Cl2 Tosylate formation (OH activation)
b R-(-)-2-methylpiperidine, K2CO3, CH3CN, 75oC, 20h Nucleophilic substitution (SN2)
c HCl 4N in dioxane, , 0oC to room temperature Secondary amine formation (Boc-deprotection)
Steps Conditions Reactions
a DIPA, BuLi -78oC, then HMPA, allyl iodide -78oC Nucleophilic substitution
b NaIO4, OsO4, iPrOH/H2O (5/1), overnight Oxidative cleavage of diol
c t-BuOK 1M in THF, THF, 30 min Spiro formation (Intramolecular cyclisation)
d Pd2(dba)3, XPHOS, t-BuONa, toluene, 90oC, 2.5h Buchwald-Hartwig reaction
e HCl 4N in dioxane, 0oC to room temperature, 1h Secondary amine formation (Boc-deprotection)
f    Cyclopentanecarboxaldehyde, NaBH(OAc)3, overnight Reductive amination
Steps Conditions Reactions
a DIPA, n-BuLi -78oC, then butenyl iodide -78oC Nucleophilic substitution
b NaIO4, OsO4, iPrOH, 6h Oxidative cleavage of diol
c 2-fluoro-4-bromoaniline, NaBH(OAc)3, Ac2O, DCE, 48h Reductive amination
d t-BuONa 1M in THF, THF, 48h Spiro formation (Intramolecular cyclisation)
e Pd2(dba)3 , XPHOS, t-BuONa, toluene, 90oC Buchwald-Hartwig reaction
f HCl 4N in dioxane, 0oC to room temperature Secondary amine formation (Boc-deprotection)
g
Furanecarboxaldehyde, NaBH(OAc)3   Reductive amination

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